The major goals of this Program Project are to determine if there is a transmissible agent associated with Alzheimer's Disease (AD) and to examine the relationship between genetically controlled parameters and the development of AD. A previously published study presented preliminary evidence that hamsters injected with buffy coat cells from some familial AD cases and their relatives developed Creutzfeldt-Jakob disease (CJD)- like changes at the clinical and histopathological levels. Whether or not an AD-associated transmissible agent played a role in the development of the diseased state in hamsters to be established. The present application describes studies that will be carried out to determine whether a transmissible CJD-like agent is in fact a causative factor in AD. Buffy coat samples will be derived from familial and sporadic AD cases, non- affected individuals from these same families, some of whom are age-range matched and others who are young and finally, a group of normal age-range matched individuals with no family history of dementia. Classification of a sample as transmissible will require that disease can be passaged from hamster to hamster. In addition to studying the transmissibility of the disease, injected hamsters will also be assessed for 1) the presence of the protease resistant protein (PrP) which is a unique marker for unconventional slow infections; 2) vacuolar morphology and ultrastructural changes in membranes; and 3) levels of phosphomonoesters and phosphodiesters. In related studies the relationship of phosphomonoesters and phosphodiesters to the events occurring in an unconventional slow infection, scrapie, will be assessed. Human buffy coat cells will be characterized by subtyping using flow cytometry and the cells will be immortalized to provide a source of nucleic acid for sequencing of the PrP coding region. These studies will determine if mutations in the PrP coding region are related to genetic susceptibility for AD. In addition, differential gene expression of PrP, ras and amyloid precursor protein genes will be monitored in freshly prepared buffy coat cells. Such studies will establish the role of genetic predisposition in the regulation and processing of these gene products and in the initiation od the disease and susceptibility to a transmissible agent. The studies described in this program project will further our understanding of the cause and mechanism of AD.